MEMS (Micro-Electro mechanical systems) based monitoring & management tools have become very popular in Neuroscience these days reason being Central Nervous system (CNS) therapeutics is most difficult to develop for the biotechnology & pharmaceutical companies. This is basically due to the "Blood Brain Barrier" but more important reason is inadequate knowledge about the detailed functioning of Nervous system & brain in normal condition & changes which occur in diseased condition.
This paper deals with the overview of a particular neurodegenerative disorder i.e. Alzheimer's disease covering all the aspects from history, progression, symptoms & conventional diagnostic & therapeutic techniques. It also highlights the role of MEMS based measurement system for EEG using Microelectrode array as well as in-vitro measurement of the various parameters using the biochemical MEA's forming an important platform for the diagnosis of Alzheimer's disease (AD). MEMS based drug delivery system holds promise for delivering the drugs across the blood brain barrier.
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Keywords: MEMS, Alzheimer's disease, Microelectrode array, Neurodegenerative disorder
Neurodegenerative disorders in simple words refer to all the disorders in which there is degeneration of neuron occurs, leading to a prolonged death. They are characterized clinically by insidious onset and progressive nervous system dysfunction. These disorders generally lead to the functional impairment which is visible with loss in cognitive, coordination, movement & sensing abilities of the subject. These symptoms are very common as exhibited in some normal disorders due to aging thus it becomes very difficult to diagnose these disorders & it becomes like a challenge for the clinicians as they are not able to confirm it with simple tests. Most of the time the subject dies due to the problems which come along due to the impairment of nervous control over that particular system. Neurodegeneration may refer to the "Degeneration of neuron" but it is the last stage of the neuronal dysfunction which already precedes the degeneration process. These disorders can be classified on the basis of the Onset time, ability of individual they affect (TABLE 1). (Institute for Neurological Disorders.2011)
In this paper we will be focusing mainly on Alzheimer's disease.
Alzheimer's is a neurodegenerative disorder which impairs memory & thinking skills of the individual, making him incapable of carrying out simplest tasks of daily living. It is the most common form of Dementia which is the general term for memory loss. The normal age of the onset of Alzheimer's is more is about 60 years. (Mattson M., 2004)( Ferri CP, Prince M, Brayne C, et al.2005)
Amylotrophic Lateral Sclerosis (ALS) or Motor Neurone Disease(MND)
It is a brain disease causing problems with the normal brain functions of thinking, memory and behaviour. It leads to the death of nerve cells and tissue resulting in the shrinkage of the tissue.
TABLE 1 : Classification of neurological disorders on the basis of the Onset time, ability of individual they affect. (Institute for Neurological Disorders.2011)
History of Alzheimer's disease
AD was discovered about 100 years ago. Several scientific breakthroughs have resulted in these past years but till today the exact cause of Alzheimer's is not known. In 1960's, scientists discovered that formation of plaques and tangles in brain affect cognitive ability of a person. In 1990's, many important discoveries were made and many researchs made it possible to somewhat understand the complex nerve cells. Â More research was focussed finding the genes responsible for AD. Treatment was symptom based and many drugs came to treat the cognitive disability. Scientists have worked in understanding the cause of AD, whether it is environmental factors, genetic factors or the formation of tangles and plaques. Some genes have been identified relating to the early-onset and late -onset of the disease but this also does not explain the cause fully. Till date there is no cure for AD, the treatment is symptom specific. (Alzheimer's disease Research)
Statistics of Alzheimer's disease
Alzheimer is spreading at a very fast pace. Today around 5.4 million Americans are suffering with this disease. This figure includes 5.2 million people whose age is more than 65(Figure 1). It is the 6th leading cause of death in America. Till today, this disease cannot be prevented, cured or ever slowed. Alzheimer causes US expenditure of around $183billion annually. Deaths from this disease have risen to around 66% in the last few years in US.
Always on Time
Marked to Standard
(Figure 1: Data obtained from AlzheimerHYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"'HYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"s disease facts and figures, 2011)
Figure 2: Expected increase of Dementia in the next 40 years span (Data obtained from AlzheimerHYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"'HYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"s disease facts and figures, 2011)
According to European Data, Dementia affects 5.4% people of total population whose age is around 65 years and its prevalence further increases with age (Ferri CP, Prince M, Brayne C, et al.2005). AD is responsible for the most of cases. Treatment of dementia costs around 21, 000 â‚¬ /year per person (Packo I.2008). According to the statistics, the number is expected to be double in the next 30 years. (Ferri CP, Prince M, Brayne C, et al.2005).
So, research in effective diagnosis and treatment of the disease and understanding the cause of the disease is in the major area of interest for scientists.
Cause of Alzheimer's disease
The cause of the disease is unknown till today however, many scientists agree that the disease probably develop as a result of multiple factors rather than a single cause. These factors include the changes in the brain and the accumulation of protein beta-amyloid outside the neurons in the brain and the accumulation of proteins tau inside the neurons. The cortex shrivels up which causes damage to the regions of thinking, planning and remembrance. Shrinkage is particularly severe in the hippocampus region, an area of the cortex that plays an important role in the formation of new memories. (Alzheimer disease HYPERLINK "http://alzheimer.ca/english/alzheimer_brain_mini_site/09.htm"&HYPERLINK "http://alzheimer.ca/english/alzheimer_brain_mini_site/09.htm" brain.2011) Ventricles also grow larger. Several other changes have also been noticed under a microscope like formation of plaques between the nerve cells and the presence of tangles in the dead nerve cells. Accumulation of protein beta-amyloid outside the neurons interferes with the neuron-neuron communication and leads to cell death. Inside the neurons due to high levels of tau proteins, tangle formation occurs blocking the supply of nutrients and other essential molecules throughout the cell. Scientists are also not sure what is the cause of death in Alzheimer's disease but the spread of plaques and tangles are the most suspected causes. Risk factors include age, heredity and family history.(HYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf" AlzheimerHYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"'HYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"s disease facts and figures, 2011)
Progression of Alzheimer's disease
The spread of AD has not yet been fully tracked still the scientist have proposed four stages in which the AD progresses in the Brain. The first stage is Mild Cognitive Impairment (MCI) & corresponds to the many symptoms such as Memory loss, which is not that much evident at the time of onset of disease. The next stage of Alzheimer is called Mild & Moderated AD, These are characterized by increasing cognitive defects & increase in dependence of patient over the caregiver leading to the total degradation of individual's personality.( Shimokawa A., Yatomib N., Anamizuc S., Toriid S., Isonod H., Sugaid Y., and Kohnoe M., 2001.)
The symptoms associated with this disorder includes memory loss causing disruptions in the normal life, challenges in planning and solving problems, difficulty completing daily tasks, confusion with time reading and place , difficulty in understanding visual images, misplacing things, poor judgement, changes in mood and personality, withdrawal from social activities. .(HYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf" AlzheimerHYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"'HYPERLINK "http://www.alz.org/downloads/Facts_Figures_2011.pdf"s disease facts and figures, 2011)
Early detection of the AD is necessary because of the following reasons (Cummings J.L., Frank J.C., Cherry D., Kohatsu N.D., Kemp B., Hewett L., and Mittman B., 2002.),( Ballard C., Lana M.M., Theodoulou M. et al, 2008),( Brookmeyer R., Johnson E., Ziegler-Graham K., and Arrighi M.H., 2007)
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Early detection helps in applying the preventive measure to treat the patient in nascent stage of AD thereby preventing the complete brain damage.
A positive diagnosis of AD gives the patient & his well-wishers time to decide about the treatment expenditures and take some future decisions.
A negative diagnosis of AD may help in relieving the anxiety due to the chances of occurrence of disease.
Early detection helps in providing the patient psychological treatment for handling the disease.
There is not a single test to diagnose the disease. It's difficult to diagnose AD, even the experts can correctly diagnose it in 90% of the cases. Diagnosis depends upon the symptoms, frequency of specific symptoms, how did these symptoms begin and how they had gone worse. The doctor also reviews the family history of the patient. Mental status tests like mini-mental state exams and mini-cog are conducted to examine the patients. Several physical examinations are also done to gain knowledge about diet, nutrition, alcohol consumption etc. Diagnosis of anaemia, diabetes, thyroid problems, kidney disorders etc. is also done. There are two main reasons for choosing neuropsychological tests for diagnosing AD: (i) There are multiple cognitive defects which are associated with AD; and (ii) Intial phases of all types of dementia is characterized by neurpsychological disorders so it is difficult to screen them. Screening tests are generally performed to find the patients who are in real need of detail investigation of the disease. The detailed list of the tests which are done for the assessment of Alzheimer's can be found in the table 2. (Hort, J., O'Brien, J. T., Gainotti, G., Pirttila, T., Popescu, B. O., Rektorova, I., Sorbi, S., Scheltens, P. and on behalf of the EFNS Scientist Panel on Dementia 2010)
Mini mental state examination(MMSE)
5 min test to examines the cognitive ability
Rey auditory verbal learning test(RAVLT)
To differentiate between patients with AD and dementia
Addenbrooke's cognitive examination(ACE)
AD verses normal control and other forms of dementia
Montreal cognitive assessment(MOCA)
Mild AD versus normal control and mild cognitive impairement(MCI)
5 words test
AD versus functional memory disorders
Table 2: Various tests used for the early detection of AD (Hort, J., O'Brien, J. T., Gainotti, G., Pirttila, T., Popescu, B. O., Rektorova, I., Sorbi, S., Scheltens, P. and on behalf of the EFNS Scientist Panel on Dementia 2010)
The most important diagnostic tools for Alzheimer's detection are the neurological examinations and brain imaging. In Neurological examinations, doctor may test the reflexes, co-ordination and balance, muscle tone and strength, eye movement, speech and sensation. Brain imaging includes structural imaging (MRI and CT) and functional imaging (PET and SPECT).
Role of Neuroimaging in Diagnosis
The structural neuroimaging techniques for the diagnosis of Alzheimer's serve dual purpose, one is to exclude the surgically treatable disease & the other is to find the specific changes related to AD. The person who suffer from AD in their early stages complain about the cognitive defects other than the memory defects, There are several structural MRI procedures which help in the detection of the atrophy in early onset of AD. Functional Neuroimaging techniques such as the Fluorodeoxy-glucose (FDG) PET & SPECT can increase the confidence in the diagnosis of the AD.FDG-PET has become the most prominently used method for detection as CT-PET is distributes at most places around the globe. It reveals many abnormalities which occur due to AD by displaying the reduced glucose metabolism in the parietal regions, superior or posterior temporal regions, inside the precuneus and posterior cingulate cortex and (Landau, S.M., et al, 2009)( Kadir, A., et al.,2010)
FDG PET is especially useful in the differentiating the diagnosis of AD from the diagnosis of other dementia, and it is successful in about 95% of early onset cases. ( Panegyres PK, Rogers JM, McCarthy M, Campbell A, Wu JS.et al, 2009). Based on the study by Foster et al. (Foster NL, Heidebrink JL, Clark CM, et al, 2007) FDG-PET is utilised in USA for differentiating between AD & Fronto-Temporal Dementia (FTD). A very progressive development is the hope of imaging amyloid Î² with the new PET ligands. Till now these are not available for routine use.
There is no cure for this disease. Treatment is basically symptom specific. Treatment may include drugs or there are some non-drug treatments also. Special medications are given for memory loss, treating the behavioural changes and sleep changes. The various drugs used for the treatment of the AD presently are (Alzheimer's society .2011)
Aricept - (donepezil hydrochloride), produced by Eisai and co-marketed with Pfizer, was the first drug to be licensed in the UK especiallyfor Alzheimer's disease.
Exelon - (rivastigmine), is produced by Novartis pharmaceuticals, was the second drug licensed in the UK especially for Alzheimer's disease.
Reminyl- (galantamine) was co-developed by Shire pharmaceuticals and the Janssen Research Foundation. Originally derived from the bulbs of snowdrops and narcissi, it was the third drug licensed in the UK specifically for Alzheimer's disease.
Ebixa- (memantine) is produced by Merz and marketed in Europe by Lundbeck. It is the newest of the Alzheimer's drugs present in the market.
Micro-Electro Mechanical Systems (MEMS)
As human expertise regarding the functionality of body & mind has increased, the complexity of the ailments which develop has also increased. Brain mapping is being used as tool for detection of disease since 1940's by (Alexander leitch, Penfield etal.1978) The recent development in MEMS (Micro-electromechanical systems such as work done in university of Washington by (Y Hanein et alÂ .2003). to acquire the signals from single neuron has emphasized on the advancement related to reducing the size of neuro-implantable devices.
As size is very important now biomedical industry is focussed on utilizing the technology of nanotubes and MEMS for the developing advance technologies for miniaturization. The sizes have reduced to micrometre range and now scientists are able to penetrate the sensing probe within the cells for accurate measurements.
There is high aspect MEMS probe of the order of few micrometre(Y Hanein et alÂ .2003)
"Many of the cells are very tiny but they are very active, they manufacture various substances; they walk around; they wriggle around; they do all kinds of marvellous things. All on very small scale consider the possibility that we can also make a thing very small which does what we want that we can manufacture an object that manuvers at that level" These words were spoken by Dr Richard Feynman, is from 1959 session of the annual meeting of American physics society.(Richard. P. Feynman .1959)
This talk was the beginning of new approach which became microelectronics & MEMS technology later on.
The three developments which mark the advancement of MEMS technology are
Silicon & IC development (Yael hanein. 2004)
Realization of VLSI & ULSI (Muzar. A. Jah. 2003)
These are the major milestones. Many other development material science & physics have elevated the today's technology quotient.
In Medical & biological systems it has become essential to monitor the biological responses more sensitively & accurately so as to control the input signals to the organism.
There are two types of electrode arrays one type are meant for receiving information from the subject, another type for transmitting the information inside the brain(i.e. stimulation). The type of electrode which are being developed for receiving information are for enquiring cardiac, neural & gastric physiology responses. The most notable & intensely researched arrays are neural electrode arrays. The neural electrode arrays & cortical electrode arrays are also different from each other as neural electrode array can be both surface as well as penetrating type whereas the cortical electrode are just surface type. There are various criterions on which a microelectrode array is judged, those are density of electrodes, flexibility of electrodes, electrode resistance, durability, biocompatibility & ease of fabrication. The density of electrodes refers to the ability of array to spatially resolve the variation between the signals over an organ. Flexibility in electrodes must be there for the minimization of trauma during the insertion of electrode as well as it provides better surface contact during measurement. Electrode impedance limits the ability of electrodes to resolve the weak voltage signals coming from the organ of interest. Durability of electrode is necessary so that the acquisition of data doesn't get compromised with the lifetime of the electrodes inside. Biocompatibility ensures that the experimental plans of research are not limited and they can be widely used and implemented according to the demand of the situation. Ease of fabrication is an important issue as it is difficult to manufacture the smaller electrode arrays with high density, thus fabrication techniques are challenged to meet the dimensions & smaller processing requirements.
Microelectrode arrays are the established mechanism to achieve the purpose, they can be defined as the spatial arrangement of the microelectrodes which are used to either gather or distribute the voltage information in the biological systems. The present goal of the microelectrode array development is to furnish arrays which can map a whole surface of brain using fine grids, So that higher resolution voltage variations & more selective inputs can be acquired.
There are a variety of MEA's available in the market for the measurement of electrophysiological signals. In most commercially available systems (Panasonic Inc., Japan, Plexus Inc., USA, GMBH, Germany) passive metal
Figure 3: High-density sensor array with 16,384 pixels based on open-gate field effect transistors on a 1Ã-1 mm2 area. a Pixel schematic. b Zoom-in on sensor array. c System architecture (Eversmann B et al 2003)
electrodes are used. These devices usually consist of 64 electrodes which are aligned on a glass or silicon substrate with externally located signal recording and filtering components for processing. CMOS technology based MEA's are prominently being used as they offer following advantages: (Eversmann B et al. 2003) ( Frey U et al. 2009) .( Hutzler M et al 2006)
Connectivity: On chip multiplexing means that data from many electrodes can be acquired, which allows measurements at high spatiotemporal resolution;
Signal quality: Signal processing circuitry is placed directly below the electrode, helping in the detection of weak signals through instantaneous signal conditioning and digitization
Ease of use: Many functions are implemented using user-friendly software that communicates with on-chip logic units through a digital interface.
Moreover, the use of CMOS technology allows the realization of small system chips which have large numbers of electrodes; arrays of up to 16,384 electrodes on 6 mm by 6 mm chips have been reported in the studies. A device based on FET transducers in CMOS technology was developed at the Max Planck Institute for Biochemistry, Germany, by the group of P. Fromherz; this CMOS MEA contains 16,384 open-gate FETs at a pitch of 7.8 Î¼m (16,000 sensors/mm2), as shown in Figure 3. The array was composed of 128Ã-128 pixels, each consisted of three transistors, each for voltage sensing, pixel selection, and calibration to compensate for transistor mismatch and leakage. The sensor chip contains a column decoder to control each pixel, a readout amplifier which amplifies for each one of the 128 rows, and an 8-to-1 multiplexer to take the outputs of the amplifiers. The generated output currents are transmitted to a set of off-chip current-to-voltage converters whose output is digitized by 16 analog-to digital converters (ADCs). To maintain high spatial resolution, a small pixel size increases the size of the circuit which are required to reduce the noise present in the system, which can range from 70 to 250 Î¼VRMS (Eversmann B et al. 2003) ( Hutzler M et al 2006)
Role of MEMS in Diagnosis of AD
MEMS Based EEG
EEG in Alzheimer's disease
Three major effects of the AD on the EEG are slowing of the EEG, reduced complexity of the EEG signals, and perturbations in EEG synchrony.
Slowing of EEG: Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) causes EEG signals to slow down.
MCI/AD is also associated with an increase of power in low frequencies (delta and theta band, 0.5-8Hz) and a decrease of power in higher frequencies (alpha and beta, 8-30Hz). How- ever, increased gamma band power (30-100Hz) has been reported in MCI/AD patients compared to healthy age-matched control subjects.
Interestingly, studies observed that the EEG of MCI and AD patients seems to be more regular (and, equivalently, less complex) than of age matched control subjects. As far as I know, no study has identified the underlying biological phenomenon. I conclude that due to the MCI/AD induced loss of neurons and perturbed anatomical and/or functional coupling, fewer neurons interact with each other, and the neural activity patterns and dynamics become simpler and more predictable. Moreover, it is possible that the MCI/AD induced condition of reduced complexity is related to slowing, since "slower" (low-pass) signals are intrinsically more regular.
There is also reduction in synchrony between the EEG signals of AD. This loss in synchrony is more often contributed to the disconnection between the neurons of cortex region. In other words it may result from anatomical disconnections among different cortical regions in combination with reduced cholinergic coupling between cortical neurons .In particular, a common hypothesis is that basal forebrain neurons may be severely affected in AD, resulting in a cerebral cholinergic deficit that leads to memory loss and other cognitive symptoms
Conventional EEG & its problems
These events in the EEG signal are not easily detectable and there is large variability among AD patients itself. As a result none of these phenomena allow at present to detect EEG at an early stage. The reason behind variability of EEG of various patients suffering from AD has been found out to be the various artefacts which occur differently in different population. Artefacts are responsible for all the false positives in assessment of AD from the EEG signal.
These artefacts caused by the:
Electromagnetic interference of power supply
EMG signal due to the Muscles
Artefacts due to blinking of eye.
Always offer problem in the EEG measurement, but when the analysis of EEG is done for detecting AD then these parameters become very crucial.
Patient is told to suppress the eye movement to reduce the artefacts due to eye movement; this thus causes the patient to give a special attention to the eye blinking thereby changing the electrical activity of the brain.
Generally it is thought that EMG signal are of high frequency and the low frequency EEG signal can be removed by passing it through the low pass filter, But it is found that certain EMG signals also are present in the low frequency range.
One more issue is the volume conduction or the blurring of the EEG caused by the spreading of the electrical signals as they move out from the cortical sources to the surface of the scalp. This spreading leads to the coupling between the electrodes being used for the measurement. Thus it becomes very difficult to relate the perturbations in the EEG signal with the physiological phenomena which cause the same. Thus these artefacts play a very important role in distorting the electrical activity measurement of a single neuron. So what can be the solution for this problem? That is the point where the Role of Microelectrode array comes into play. Intracranial EEG (IEEG) as well as surface EEG based on MEMS play a crucial role these days in development of a hypothesis regarding the occurrence of disease
Role of Microelectrode array in Measurement of EEG
There are two ways to obtain the EEG signal: non-invasive way and invasive way. Non-invasive way is to place the electrodes on the scalp to record EEG signals including biofeedback training signal and induced signal. Its advantage is the EEG signal can be enhanced by action training or biofeedback training, and its disadvantage is it needs external stimulus signal and long training time. Invasive way is to place the microelectrodes in the cerebral cortex to collect EEG signal from single neurons or a minimum group neurons. Compared with the signal obtained in non-invasive way, the signal obtained in invasive way is higher signal-to-noise ratio (SNR)[1-3].
Bio-potential Electrodes which are used to measure the electrical potential produced by the neurons present inside brain convert the electrical potential obtained from the skin surface of scalp into electrical current in the amplifier circuit. Therefore the most important characteristic of the electrode must be low electrode-skin interface impedance so that the electrical potential is able to propagate through the skin without any attenuation or noise. MEMS based dry EEG electrodes are the most suitable electrode to be used in such condition as if the electrolytic gel based electrodes are used, then it will harden in few hours thereby changing the conductivity of electrical potential through the skin. Thus it becomes important to use dry electrode which are helpful in long term monitoring. These electrode are formed as an array therefore called as Microelectrode array
EEG measurement using the microelectrode array offers a better spatial resolution as compared to the conventional methods of the measurement of EEG. Better source localization is achieved if the electrodes are placed closer to the tissue, either in direct contact with the surface of tissue or it is directly penetrating into it. Studies which have been performed on rodent's brain have shown that surface field potentials which is measured using the smaller electrodes of the size (150Î¼m) can effectively map the representations of cortical activation & EEG surface potentials with high temporal & spatial resolution.[Jones MS, 1999].
High-density microelectrode arrays realized in standard CMOS technology offer the potential to perform recordings at single-cell or even subcellular resolution .When designing such systems, a compromise between noise performance and spatial resolution must be made. To achieve high spatial resolution, small electrodes are preferred; unfortunately, thermal noise is inversely correlated to electrode size.
These array help in the continuous measurement of the EEG signal as well because they can be interfaced to the wireless transmission systems for external monitoring, they are weightless & patient can easily carry them in their head while doing their normal work.
Regarding the IEEG, Penetrating microelectrode arrays have been used extensively in animal studies but their use with humans has been limited (Burmeister, 2002; Heppelmann, 2001; Waren, 2001). As a result of the associated potential risks, studies utilizing penetrating microelectrode arrays with humans have only involved areas of cortex that are destined for surgical resection (Bechtereva , 2000; Oya, 2002; Schwartz, 2000; Williamson, 1993)
Advantages & Usefulness of EEG in detection of AD
EEG is an appealing modality for diagnosing AD, since EEG recording is inexpensive & potentially mobile as well as beneficial for continuous monitoring of AD. Moreover, EEG as compared to other non-invasive brain imaging modalities, it has higher temporal resolution as well as useful information related to the abnormal dynamics of brain in case of patients suffering from AD.
Biochemical Microelectrode array for AD
Microelectrode arrays were used for the in-vitro diagnosis of the AD. As per (Kucku Varghese etal .2009).As soluble oligomers of amyloid beta (AÎ²) are the one of the major contributing factors in the development of AD. Most therapeutic studies focussed on functional toxicity. AÎ² also inhibit the spontaneous firing of hippocampal neurons without noticeable cell deaths at very low concentrations. But this toxicity leads to the degeneration of synapses as well which is more evident when functions of the body start getting deteriorated proceeding to this synapse loss. When the cells are applied to hippocampal neurons incorporated on MEAs, AÎ² had a high effect on the instantaneous firing of the cells. This study demonstrated that it is possible to develop a high-throughput screen for the measurement of a drug's effect on functional toxicity of low concentrations of AÎ² and this model is the first step for an in vitro functional model of the development of AD. This screening method, based on MEA technology, could find important applications in pharmaceutical drug development and could lead to novel drug candidates or therapies for AD.
Conclusions & Future prospective
EEG studies alone cannot give us a desirable Biophysical knowledge about AD.197 detailed mathematical models of AD along with the EEG data analysis can give us an insight about pathology of AD. In the same lines EEG can be combined with the other modalities such as Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), Doppler techniques, Transcranial Magnetic Stimulation (TMS) & Single Photon Emission Computed Tomography (SPECT).
MEMS based Transcranial drug delivery system in AD
The development of drug for the AD is still in its naÃ¯ve stage because of the inability of the drugs to pass through Blood Brain Barrier(BBB).Other than that there is an imbalance between the resources which are being use to find the treatment of AD. 99% of the research is going on & working towards finding the drug which would treat Alzheimer & 1 % research is involved in finding the novel drug for the treatment of AD.
The current problems due to BBB in drug delivery are as follows
More than 98% of the drugs whose molecular size is small are not able to pass through BBB
And about 100%of drugs whose molecular size is large, i.e., the products of biotechnology, are also not able to cross the BBB
No Big Pharmaceutical industry in the world today has a BBB drug targeting program
Transcranial drug delivery is the only option left for the delivery of the drugs to the CNS directly, But it is difficult to develop the methods which involves the delivery of drugs without any damage to the cranium, no scar development and along with that no evoked response from the body.
MEMS play a very important role in this transcranial drug delivery across the Blood Brain Barrier (BBB). MEMS based device which have the ability to deliver the drug without damaging the BBB which makes the BBB susceptible to other diseases as well .It can help in providing controlled drug delivery to the CNS with the external control implemented to it.